PROJECT SUMMARY Upper respiratory tract infections (URIs) are the most common infectious illnesses in the United States and the world. The vast majority of these infections are caused by rhinovirus and influenza viruses that infect respiratory epithelial cells, compromise their barrier function, and initiate an inflammatory response that produces clinical pathology. Complications associated with URIs are among the leading causes of mortality worldwide. Current treatment strategies primarily involve 1) agents that address symptoms and do not reduce the duration or severity of disease or 2) a systemic antiviral (for influenza only) which causes significant undesirable side effects. We have developed novel, topical antiviral treatments that effectively inhibit replication of rhinovirus (HRV) and influenza (IV) in a fully differentiated, human nasal epithelial cell model. Our approach combines viral inhibitors with innate immune factors to achieve synergistic control of infection. In this proposal, we plan to build on our promising preliminary results to 1) Assess the efficacy of a combined anti-HRV and anti-IV antiviral, and 2) Measure the inflammatory response to infection and treatment to assess the efficacy and safety of our treatment in preventing the release of cytokines that drives clinical symptoms and adverse events. !